TRPM8 levels determine tumor vulnerability to channel agonists

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Precision oncology relies on identifying actionable targets for targeted therapies.
• Current targeted therapies are limited by the availability of specific molecular targets in cancer cells.

Purpose of the Study:

• To investigate the role and potential of the TRPM8 channel as a therapeutic target in multiple cancer types.
• To evaluate the synergistic effect of TRPM8 activation with chemotherapy.

Main Methods:

• Comparative analysis of TRPM8 expression in lung, breast, colorectal, and prostate cancer cell lines.
• Assessment of the cytotoxic effects of TRPM8 agonist D-3263 combined with chemotherapy in cancer cell lines and patient-derived organoids.

Main Results:

• High TRPM8 channel expression was observed in the core of all four analyzed carcinomas, independent of RNA levels.
• Sub-lethal chemotherapy dosages combined with the TRPM8 agonist D-3263 demonstrated a synergistic lethal effect on cancer cell lines.
• D-3263 enhanced the cytotoxicity of 5-FU/Oxaliplatin in colorectal cancer organoids, correlating with TRPM8 expression levels.

Conclusions:

• TRPM8 is a strong candidate molecular target for precision oncology strategies.
• The findings support the development of clinical trials targeting TRPM8 in TRPM8-high tumors.